Approximately 2.5 million Americans live with epilepsy and epilepsy-related deficits today, more than disabled by Parkinson disease or brain tumors. The impact of epilepsy in the US is significant with a total cost to the nation for seizures and epilepsy of approximately $12.5 billion. Epilepsy consists of more than 40 clinical syndromes affecting 40 million people worldwide. Approximately 25 percent of individuals receiving antiepileptic medication have inadequate seizure control; however, 80% individuals with medication resistant epilepsy might be cured through surgery if one were able to precisely localize the seizure focus. The proposed research will significantly advance our ability to localize such foci, and thereby offer curative epilepsy surgery for this devastating disease. We hypothesize that diffuse optical tomography (DOT) provides a new functional and cellular neuroimaging modality for non-invasively tracking dynamical changes during seizure occurrence. DOT has the ability to image tissue functions including oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), cerebral blood volume (CBV), cerebral blood flow (CBF) and rate of cerebral oxygen metabolism (CMRO2). In addition, we show that DOT can also provide cerebral cellular morphology that is derived from tissue scattering spectra. Given the high temporal and spatial resolution for optical modalities, the proposed hemodynamic and cellular imaging will offer unprecedented localization of both ictal and interictal seizure activities, a feature that is unavailable from any of the existing neuroimaging techniques. While the primary goal of this project is to develop a DOT system for accurate localization of epileptic focus, we also propose to study the neuro-vascular and neuro-cellular coupling between neuronal activity and hemodynamic/cellular response using concurrent electroencephalography (EEG) and DOT noninvasively in animal models of seizure. Such coupling study is becoming increasingly important for interpreting functional/cellular imaging results, and may be useful in predicting seizure onset. To test the hypothesis, we propose to complete the following specific aims: (1) To design, construct and test a fast multispectral optical system for functional/cellular DOT imaging; (2) To develop a set of image enhancement schemes for improved DOT imaging of small animals, and To develop both linear and nonlinear models that couple the electrophysiological recordings with the hemodynamic/cellular response measured by DOT; (3) To evaluate and optimize the integrated functioning of the hardware and software components of the multispectral DOT system, using simulation and phantom experiments; (4) To test and evaluate the proposed DOT system and neuro-vascular/neuro-cellular coupling models using animal models.